Lipin-1 contributes to IL-4 mediated macrophage polarization

Chandran, Sunitha; Schilke, Robert M; Blackburn, Cassidy M.R.; Yurochko, Aila; Mirza, Rusella; Scott, Rona S.; Finck, Brian N.; Woolard, Matthew D.

doi:10.1101/2019.12.23.887109

Cited by 8 publications

(27 citation statements)

References 35 publications

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“…Mice lacking lipin-1 enzymatic activity in myeloid cells (Lipin-1mEnzy KO) had reduced plaque size compared to wild type mice suggesting lipin-1 enzymatic activity is atherogenic [1]. In contrast, we have demonstrated that lipin-1 transcriptional coregulatory activity likely promotes wound healing responses in macrophages [24]. Figure 1: Lipin-1 localizes to the nucleus in bone marrow-derived macrophages Femurs were isolated from wild type mice.…”

Section: Lipin-1 Transcriptional Co-regulatory Activity Is Involved Imentioning

confidence: 92%

“…The plaque size in the lipin-1m KO mice was nearly twice as large as the littermate control mice. Lipin-1m KO macrophages had decreased pro-resolving, wound healing macrophage polarization [24]. We hypothesized that myeloid-associated lipin-1 transcriptional co-regulatory activity promotes anti-inflammatory responses within the atherosclerotic plaque.…”

Section: Increased Expression Of Collagen and Pro-inflammatory Genes mentioning

confidence: 99%

“…The isoforms are lipin-1, lipin-1-, and lipin-1. Lipin-1 has only been detected in the brain; however, lipin-1, and lipin-1 have been detected in other hepatocytes, adipocytes, and macrophages [12,13,16,17,20,24,30]. There are two bands in the cytosolic fraction (one faint band and one dark band) and there are two prominent bands in the nuclear fraction for lipin-1.…”

Section: Lipin-1 Localizes To the Nucleus In Bone Marrow-derived Macrmentioning

confidence: 99%

“…Lipin-1 is a phosphatidic acid phosphohydrolase that converts phosphatidic acid into diacyglycerol during glycerolipid synthesis [1,[12][13][14][15][16][17]. Lipin-1 is also a transcriptional coregulator that enhances the expression of genes related to beta-oxidation [18][19][20][21]. Lipin-1 binds and increase the activity of transcription factors PPAR-, PGC-1, PPAR-.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously demonstrated that lipin-1 can locate to the nucleus of macrophages with an atherosclerotic plaque, suggesting that lipin-1 transcriptional co-regulatory activity contributes to macrophage responses during atherosclerosis [14]. Nuclear lipin-1 contributes to IL-4 mediated macrophage responses and aids in wound healing [24]. Lipin-1 transcriptional co-regulatory activity augments PPARs to enhance anti-inflammatory responses and fatty acid oxidation genes in cells such hepatocytes and adipocytes [18,20,25,26].…”

Section: Introductionmentioning

confidence: 99%

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Macrophage-associated lipin-1 transcriptional co-regulatory activity is involved in atherosclerosis

Blackburn

Schilke

Vozenilek

et al. 2020

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During atherosclerosis, macrophages engulf and break down deposited modified lowdensity lipoproteins (modLDLs) into lipids and free fatty acids. The lipids and free fatty acids from these modLDLs either need to be stored during a process called glycerolipid synthesis or broken down during -oxidation. In addition, free fatty acids can activate transcription factors to promote a pro-resolving macrophage phenotype. The protein lipin-1 is involved in both glycerolipid synthesis and β-oxidation. Lipin-1 enzymatic activity is a key step in the glycerolipid synthesis pathway; lipin-1 transcriptional co-regulatory activity either augments or represses various transcription factors that are activated via free fatty acids that promote -oxidation and inhibit inflammation. Lipin-1 enzymatic activity increases pro-inflammatory macrophage phenotypes and is atherogenic. In contrast, we have also demonstrated that lipin-1 transcriptional co-regulatory activity promotes proresolving macrophage phenotypes leading us to the hypothesis that lipin-1 transcriptional co-regulatory activity is atheroprotective. Using a mouse model to delete lipin-1 in myeloid cells, we have demonstrated that loss of lipin-1 increases plaque size and proinflammatory gene expression. We have also shown mice lacking lipin-1 in myeloid cells have increased plaque collagen deposition and larger necrotic core formation. Combined, these data suggest that though lipin-1 enzymatic activity is atherogenic, lipin-1 transcriptional co-regulatory activity is atheroprotective. Overall, the results suggest that the dual activities of lipin-1 contribute to atherosclerosis progression in opposite ways. Introduction:

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Section: Lipin-1 Transcriptional Co-regulatory Activity Is Involved Imentioning

confidence: 92%

Section: Increased Expression Of Collagen and Pro-inflammatory Genes mentioning

confidence: 99%

Section: Lipin-1 Localizes To the Nucleus In Bone Marrow-derived Macrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Macrophage-associated lipin-1 transcriptional co-regulatory activity is involved in atherosclerosis

Blackburn

Schilke

Vozenilek

et al. 2020

Preprint

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An anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury in zebrafish

et al. 2022

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Macrophages are essential for tissue repair and regeneration. Yet, the molecular programs, as well as the timing of their activation during and after tissue injury are poorly defined. Using a high spatio-temporal resolution single cell analysis of macrophages coupled with live imaging after sensory hair cell death in zebrafish, we find that the same population of macrophages transitions through a sequence of three major anti-inflammatory activation states. Macrophages first show a signature of glucocorticoid activation, then IL-10 signaling and finally the induction of oxidative phosphorylation by IL-4/Polyamine signaling. Importantly, loss-of-function of glucocorticoid and IL-10 signaling shows that each step of the sequence is independently activated. Lastly, we show that IL-10 and IL-4 signaling act synergistically to promote synaptogenesis between hair cells and efferent neurons during regeneration. Our results show that macrophages, in addition to a switch from M1 to M2, sequentially and independently transition though three anti-inflammatory pathways in vivo during tissue injury in a regenerating organ.

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Lipin-1 regulates lipid catabolism in pro-resolving macrophages

Schilke

Blackburn

Rao

et al. 2020

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24Macrophages reprogram their metabolism to promote appropriate responses. Pro-resolving 25 macrophages primarily utilize fatty acid oxidation as an energy source. Metabolites generated during the 26 catabolism of fatty acids aid in the resolution of inflammation and tissue repair, but the regulatory 27 mechanisms that control lipid metabolism in macrophages is not fully elucidated. In this current study we 28 show that lipin-1, a phosphatidic acid phosphatase and regulator of lipid metabolism, is required for 29 increased oxidative phosphorylation during IL-4 mediated responses. We also show that the 30 transcriptional coregulatory function of lipin-1 is required for β-oxidation in response to palmitate (free 31 fatty acid) and apoptotic cell derived lipids. BMDMs lacking lipin-1 have a reduction in critical TCA 32 cycle metabolites following IL-4 stimulation, suggesting a break in the TCA cycle that is supportive of 33 lipid synthesis rather than lipid catabolism. Together, our data demonstrate that lipin-1 regulates 34 intermediary metabolism within pro-resolving macrophages and highlights the importance of aligning 35 macrophage metabolism with proper responses to stimuli. 36 37 3Introduction: 38 Macrophages are innate immune cells that regulate tissue homeostasis and are critical for disease 39 resolution. Macrophages are able to polarize toward distinct phenotypes, such as pro-resolving 40 macrophages (M2) macrophages that aid in wound healing processes [1, 2]. As macrophages polarize, they 41 change their metabolic profile to effectively respond to stimuli[3]. Pro-inflammatory macrophages 42 predominately rely on glycolysis to generate ATP. Oxidative phosphorylation is reduced to generate 43 reactive oxygen species and promote lipid synthesis[4]. Pro-inflammatory macrophages have a break in 44 the TCA cycle at two distinct points. The first break leads to the accumulation of citrate, which is exported 45 out of the mitochondria to be used in lipid synthetic pathways. The second break leads to the accumulation 46 of succinate which stabilizes HIF1α to increase expression of pro-inflammatory genes. Pro-inflammatory 47 macrophages also increase the pentose phosphate pathway (PPP) to generates NADPH, which is used in 48 lipid synthesis and cellular redox potential[5]. Pro-resolving macrophages initially increase glycolysis to 49 quickly generate ATP, but heavily rely on oxidative metabolism to produce sufficient energy to carry out 50 their functions. Pro-resolving macrophages utilize β-oxidation of fatty acids to produce acetyl-CoA, which 51 is oxidized via a series of reaction in the TCA cycle. The oxidation of acetyl-CoA generates reducing 52 equivalents, such as NADH, to fuel the electron transport chain[5]. B-oxidation has been shown to 53 promote macrophage polarization towards the pro-resolving phenotype, and is essential to disease 54 resolution [6]. Catabolism of apoptotic cell derived lipids promotes IL-10 production and subsequent 55 wound healing in a mouse model of myocardial infarction[6]. ...

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Lipin-1 contributes to IL-4 mediated macrophage polarization

Cited by 8 publications

References 35 publications

Macrophage-associated lipin-1 transcriptional co-regulatory activity is involved in atherosclerosis

Macrophage-associated lipin-1 transcriptional co-regulatory activity is involved in atherosclerosis

An anti-inflammatory activation sequence governs macrophage transcriptional dynamics during tissue injury in zebrafish

Lipin-1 regulates lipid catabolism in pro-resolving macrophages

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